My overall goal is to become an independent scientist in the obesity and diabetes field. As a postdoctoral fellow in Dr. Kahn's laboratory in the Endocrine Division at Beth Israel Deaconess Medical Center in Boston my research has focused on the role of protein tyrosine phosphatases (PTPs) in the pathogenesis of insulin resistance. Obesity, an insulin-resistant state, is a risk factor for developing type 2 diabetes. Increased expression or activity of PTP1B, observed in muscle and adipose tissue of obese, insulin-resistant animals and humans, may cause insulin resistance. Conversely, we found that PTP1B deficient (PTP1B-/-) mice have increased insulin sensitivity in muscle and liver. To determine whether PTP1B overexpression in muscle contributes to insulin resistance, we generated transgenic mice overexpressing PTP1B at low levels, similar to the levels observed in muscle of insulin resistant animals and humans. Preliminary data suggest that overexpression of PTP1B causes mild insulin resistance. In Aim 1, I will fully characterize insulin action and body weight regulation in these mice. PTP1B-/- mice are also lean and resistant to diet-induced obesity. Our preliminary data suggest that leanness of PTP1B-/- mice is due in part to leptin hypersensitivity and that PTP1B negatively regulates leptin signaling in hypothalamus in vivo. My goal for this award is to obtain the necessary training in neuroscience and neuroendocrinology to determine the mechanism by which PTP1B regulates adiposity and energy balance. To determine whether PTP1B action on insulin and/or leptin signaling in hypothalamus regulates adiposity in vivo, we will generate transgenic mice overexpressing PTP1B selectively in neurons in Aim 2 and PTP1B-/- mice with restored expression of PTP1B selectively in neurons in Aim 3. The effects on adiposity and insulin sensitivity will provide important insights into the biological role of PTP1B in regulating whole body insulin sensitivity and adiposity. Pursuing these studies at BIDMC with Dr. Kahn, an expert in characterizing animal models of obesity and diabetes, and Dr. Elmquist, an expert in mapping leptin-responsive pathways in the CNS, will provide an exemplary environment for my research.